The onset and/or severity of illness in mammals is related to the level of stress experienced by that mammal. In patients who are ill, either hypo- or hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis has been observed, which activity represents the physiological regulator of the stress response in mammals.
Regulation of HPA occurs via a multifaceted integrated mechanism, wherein corticotropin-releasing factor (CRF) and vasopressin (AVP) produced by the brain are believed to stimulate production of adrenocorticotropin tropin (ACTH) from the anterior pituitary, the primary inducer of cortisol secretion. Cortisol so produced has a negative influence upon ACTH secretion thus providing a feedback regulatory mechanism within this system.
An additional ACTH-inhibiting factor is postulated by Grossman and Tsagarakis (1989, J. Endocrinology, 123:169-172), which is termed corticotropin release inhibiting factor (CRIF or CIF), see Redei et al., In: Neuropeptides and Stress, Eds. Tache et al., Hans Selye Symposia on Neuroendocrinology and Stress, 1989, Springer-Verlag, New York). This activity comprises an unidentified hypothalamic peptide, which peptide exhibits inhibitory activity on basal and CRF or stress stimulated ACTH secretion both in vitro and in vivo (Redei et al., 1984, In: Integrative Neurohormonal Mechanism Developments in Neuroscience, Vol. 16, Eds. Endroczi et al, Elsevier, Amsterdam).
A hypothalamic peptide fraction isolated from both pigs and rats was found to contain CRIF activity. When injected into rats, it suppressed corticosterone (CORT) response to footshock (Redei et al., 1984, In: Integrative Neurohormonal Mechanism Developments in Neuroscience, Vol. 16, Eds. Endroczi et al, Elsevier, Amsterdam). In addition, a peptide fraction (molecular weight 0.6-2.3 kDa) has been isolated from bovine hypothalamus which exhibits CRIF activity both in vitro and in vivo (Redei et al., In: Neuropeptides and Stress, Eds. Tache et al., Hans Selye Symposia on Neuroendocrinology and Stress, 1989, Springer-Verlag, New York).
There has been a long felt need to determine the identity of CRIF because of its important relationship in regulating ACTH production. Compounds which act as agonists or antagonists of CRIF activity, or CRIF itself, are useful for diagnosis and treatment of a variety of diseases associated with stress responses. Such diseases include, but are not limited to, depression, obsessive compulsive disorders, anxiety, withdrawal from drug addiction, autoimmune diseases and even premenstrual syndrome. Such diseases also include cancers whose initiation and/or progression are influenced by the mental state of the individual, which mental state is a reflection of the level of compounds, such as hormones and glucocorticoids, which are either over- or underproduced in that individual. The level of these compounds may be affected by CRIF or a CRIF agonist or antagonist.
In addition, such CRIF peptides and nucleic acids and antibodies related thereto are useful as diagnostic reagents for determination of CRIF-related disease states.